Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4866—Organic macromolecular compounds
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
  • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
  • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
  • C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P7/00—Preparation of oxygen-containing organic compounds
  • C12P7/62—Carboxylic acid esters

Definitions

• This invention relates to polyoxyalkylene glycols (in the following sometimes referred to as POAG) or monoalkylated polyoxyalkylene glycols esterified with O-acylated, O-alkylated or O-alkenylated hydroxy fatty acids, as well as their manufacture, their use in formulations (including pharmaceutical formulations), and their use as surfactants.
• POAG polyoxyalkylene glycols
• HTS methods High Throughput Screening
• candidate drugs with a low aqueous solubility.
• pharmaceutical formulators In order to minimise administration volumes and obtain a high bioavailability it is of great practical importance for pharmaceutical formulators to have the ability to increase the solubility of these compounds when suitable dosage forms are developed.
• These preparations can be intended both for assessment of medical effect in humans and safety studies in animals during the development of a new drug, and as the final pharmaceutical dosage form for the marketed product.
• micellar systems are the stability over a wide composition range, simplicity of preparation, low viscosity and the fact that a micellar system is a thermodynamically stable single phase which is optically clear.
• Surfactants can be divided into anionic, e.g. sodium lauryl sulfate, cationic, e.g. cetyl trimethyl-ammonium bromide, zwitter-ionic, e.g. alkyl betaines and non-ionic surfactants, e.g. ethoxylated sorbitanoleate, according to their chemical properties.
• surfactants for use in pharmaceutical applications depends to some extent on the route of adminstration and is rather limited since most surface-active compounds are not tolerated well enough for pharmaceutical use.
• ionic surfactants are not suitable since these cause hemolysis of red blood cells and destruction of T lymphocyte cells at low concentrations. [“Solubility & Solubilization in aqueous media.”, Yalkowsky, 1999].
• the most accepted surfactants for parenteral use are phospholipids and non-ionic surfactants.
• non-ionic surfactants are usually preferred but ionic-surfactants have been used in low concentrations.
• Non-ionic surfactants used in pharmaceutical applications today include substances/mixtures such as ethoxylated castor oil (Cremophor EL), ethoxylated sorbitan fatty acid esters, e.g. polyoxyethylene sorbitan monooleate (Tween 80), sorbitan fatty acid esters, e.g. sorbitan monooleate (Span 80), ethoxylated hydroxystearic acid, e.g. polyethylene glycol 660 (12-)hydroxystearate (Solutol HS15), etylene and propylene oxide block copolymers (Pluronic F68) and fatty acid esters of glycerol (Imwitor 742).
• ethoxylated castor oil Cosmetic EL
• ethoxylated sorbitan fatty acid esters e.g. polyoxyethylene sorbitan monooleate (Tween 80)
• sorbitan fatty acid esters e.g
• the commercial non-ionic surfactants available for pharmaceutical formulators are complex mixtures of different molecules which makes the characterisation of these products very difficult, giving an expensive and tedious analytical process to ensure adequate quality (for i.a. pharmaceutical applications).
• non-ionic surfactants systems used for parenteral administration are all based on polyethylene glycol derivatives. Although there are several pharmaceutical products for parenteral administration on the market containing these surfactants, they all suffer from quite severe side effects, like release of histamine which in severe cases can lead to anaphylactic chocks (Lorentz et al., Agents and Actions, Vol. 12, 1/2, 1982).
• Histamine release is believed to be caused by impurities in the commercial products and since the non-ionic surfactants used are very complex mixtures of different molecules it is not possible to purify existing products. Also in such situations it is hard to relate any side-effects to a particular molecule. (Vulfsson. In “Novel Surfactants”. Holmberg editor. Marcel Dekker 1988. p. 279-97.)
• the products formed are mixtures of monoesters or diesters of polyetylene glycol (PEG) and monohydroxy fatty acids or estolides, the latter commonly known as a generic name for linear oligomeric polyesters of hydroxyl fatty acids wherein the carboxyl group and hydroxyl group of hydroxyl fatty acids are dehydrated to form oligomers.
• PEG polyetylene glycol
• monohydroxy fatty acids or estolides the latter commonly known as a generic name for linear oligomeric polyesters of hydroxyl fatty acids wherein the carboxyl group and hydroxyl group of hydroxyl fatty acids are dehydrated to form oligomers.
• the products of EP 0017059A1 comprising two or more monohydroxy fatty acids where the monohydroxy fatty acid of the estolide may either be attached directly to the hydroxyl group of another fatty acid or to a hydroxyl group of a PEG chain attached to the aforementioned hydroxyl group of a monohydroxy fatty acid.
• Solutol HS 15 is such a product.
• Short PEG chains one type of polyoxyalkylene glycol, or POAG, chain
• POAG polyoxyalkylene glycol
• U.S. Pat. No. 6,365,637 claims the use of esters or amides of hydroxylated carboxylic acids as solubilizers, for i.a. pharmaceutical purposes. These compounds all have short PEG chains. Furthermore, the optional use of a dimerized fatty acid, as described in U.S. Pat. No. 6,365,637, of commercial quality including both monomeric, dimeric, trimeric and higher polymerized acids in the synthesis is a draw-back when one desires to obtain highly pure compounds.
• compositions such as tablets, capsules, powders, dispersions, emulsions, rectal formulations like suppositories and also in solutions.
• they can be used as e.g. media for making solid dispersions, absorption enhancers, emulsifiers in emulsions and microemulsions, dispersing agents in solid dispersions, emulsifier in self-emulsifying systems, lubricants in tablet pressing, wetting agents in granulation processes, vehicles in spray-drying compositions etc, are also uses, not limited to any particular administration route, that are contemplated in this invention.
• lipase B from Candida antarctica or an equivalent can be used.
• This enzyme is particularly beneficial to employ to obtain more homogenous reaction products.
• Another advantage is that it makes it possible to employ a reaction for this esterification step that is free from organic solvents.
• the compounds of the invention surprisingly having the beneficial advantages of better tolerability, low hemolytic activity, possibility to be produced with higher purity and having high solubilization capacity, have chemical structures as described in formula (I) below;
• the compounds are based on an acylated/alkylated/alkenylated hydroxy fatty acid forming an ester bond with a poly (oxyalkylene) glycol [in a shorter form POAG] or monoalkylated poly (oxyalkylene) glycol on the carboxylic group end.
• the R 1 group positioned on the outer end of the POAG chain may be H or C 1 -C 4 alkyl.
• R 1 is H, alternatively R 1 is C 1 -C 4 alkyl.
• the R 1 is H or C 1 -C 2 alkyl.
• R 1 is C 1 -C 2 alkyl.
• the R 1 is methyl.
• POAG includes poly (oxyethylene) glycols, commonly known as i.a. PEG's, and poly (oxypropylene) glycols, commonly known as PPG's.
• the oxypropylene units may be linear or branched.
• R 3 is chosen among ethylene, propylene or branched propylene.
• the POAG chain used in the invention has preferably, counted as poly (ethylene) glycol, an average molecular weight of 1100-20000. More preferred is to use a POAG with an average molecular weight of 1100-10000, most preferred is to use a POAG with an average molecular weight of 1100-2500, all these average molecular weights counted as for poly (ethylene) glycol.
• the poly (oxyalkylene) glycols or monoalkylated poly (oxyalkylene) glycols used are of pure, monodisperse or polydisperse commercial quality.
• polyoxyalkylene glycol e.g. PEG
• chain average molecular weight corresponds to values of z being 25-455, preferably 25-228 and most preferably 25-57.
• Table 1 shows the relation between z and average molecular weight for PEG and PPG, respectively.
• the carbon chain in the hydroxy fatty acid part of the inventive compounds are characterized in that the oxygen from the hydroxy group is positioned such as that x is 2-18 and y is 1 to 17, while the sum of (x+y), defining the length of the hydroxy fatty acid carbon chain, is 3-19.
• x is 2-15 and the value of y is 4-17, while the sum of (x+y) is 6-19.
• x is 2-12 and the value of y is 7-17, while the sum of (x+y) is 9-19.
• the oxygen in the hydroxyl group on the HFA residue is connected (via an ester linkage or ether linkage) to a group R 2 , R 2 being C 14 to C 22 , linear or branched, acyl, alkyl or alkenyl wherein the acyl, alkyl or alkenyl may be optionally further substituted with one or more of the following (independently selected); halogen, cyano, carboxy, carbamoyl, carbamoyl(C 1 -C 4 )alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, mercapto, nitro, amino, (C 1 -C 4 )alkylamino, phenyl, naphthyl, phenyloxy, naphthyloxy, (C 1 -C 4 )alkylthio, or (C 1 -C 4 )alkylsulfinyl.
• R 2 is unsubstituted. In another embodiment R 2 is substituted by one or two substituents, preferably one.
• the R 1 group positioned on the outer end of the POAG chain is C 1 -C 4 alkyl. In one more preferred second embodiment of the invention, R 1 is C 1 -C 2 alkyl. In the especially most preferred second embodiment R 1 is methyl.
• POAG includes poly (oxyethylene) glycols and poly (oxypropylene) glycols.
• the oxypropylene units may be linear or branched.
• R 3 is chosen among ethylene, propylene or branched propylene.
• the POAG chain used in the invention has preferably, counted as poly (ethylene) glycol, an average molecular weight of 1100-20000. More preferred is to use a POAG with an average molecular weight of 1100-10000, most preferred is to use a POAG with an average molecular weight of 1100-2500, all these average molecular weights counted as for poly (ethylene) glycol.
• the poly (oxyalkylene) glycols or monoalkylated poly (oxyalkylene) glycols used are of pure, monodisperse or polydisperse commercial quality.
• polyoxyalkylene glycol e.g. PEG
• z preferably 25-455, more preferably 25-228 and most preferably 25-57.
• Table 1 above shows the relation between z and average molecular weight for PEG and PPG, respectively.
• the carbon chain in the hydroxy fatty acid part of the inventive compounds are characterized in that the oxygen from the hydroxy group is positioned such as that x is 2-18 and y is 1 to 17, while the sum of (x+y), defining the length of the hydroxy fatty acid carbon chain, is 3-19.
• x is 2-15 and the value of y is 4-17, while the sum of (x+y) is 6-19.
• x is 2-12 and the value of y is 7-17, while the sum of (x+y) is 9-19.
• the oxygen in the hydroxyl group on the HFA residue is connected (via an ester linkage or ether linkage) to a group R 2 , R 2 being C 14 to C 22 , linear or branched, acyl, alkyl or alkenyl wherein the acyl, alkyl or alkenyl may be optionally further substituted with one or more of the following; halogen, cyano, carboxy, carbamoyl, carbamoyl(C 1 -C 4 )alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, mercapto, nitro, amino, (C 1 -C 4 )alkylamino, phenyl, naphthyl, phenyloxy, naphthyloxy, (C 1 -C 4 )alkylthio, or (C 1 -C 4 )alkylsulfinyl.
• R 2 is unsubstituted. In another second embodiment R 2 is substituted by one or two substituents, preferably one.
• the synthesis can, for example, be performed by starting from the hydroxy fatty acid or its C 1 -C 4 alkyl esters. If needed, the hydroxy fatty acid starting material may be purified by a suitable method, e.g. extraction or chromatographic methods. This is beneficial for obtaining the best results of the invention.
• Esterification of the fatty acid hydroxyl group can for example be performed with an acyl chloride.
• the two reactants are mixed in a suitable solvent, e.g. methyl tert-butyl ether (MTBE) containing pyridine in a suitable concentration e.g. 1.5 equivalents, in relation to the acyl chloride.
• a suitable solvent e.g. methyl tert-butyl ether (MTBE) containing pyridine in a suitable concentration e.g. 1.5 equivalents, in relation to the acyl chloride.
• MTBE methyl tert-butyl ether
• Purification of this product can for example be done by extraction.
• the product is first washed with a weakly acidic solution, e.g. 1% sulphuric acid, and then with a weakly basic solution, e.g. saturated aqueous sodium bicarbonate.
• a weakly acidic solution e.g. 1% sulphuric acid
• a weakly basic solution e.g. saturated aqueous sodium bicarbonate.
• further purification may be done using a chromatographic method, e.g. preparative silica gel chromatography.
• the synthesis can, for example, be performed by starting from esters of the hydroxy fatty acid. If needed, the hydroxy fatty acid ester may be purified by a suitable method, e.g. extraction or chromatographic methods. This is beneficial for obtaining the best results of the invention.
• Etherification of the fatty acid hydroxyl group with an alcohol can for example be performed in two steps.
• the first step may consist of reacting the alcohol with toluene-4-sulfonyl chloride in a suitable solvent, e.g. dichloromethane, containing pyridine in a suitable concentration e.g. 1.5 equivalents in relation to the toluene-4-sulfonyl chloride.
• Purification of the produced alcohol toluene-4-sulfonate can for example be done by extraction.
• the product is then washed with a weakly acidic solution, e.g. 1% sulphuric acid. If needed, further purification may be done using a chromatographic method, e.g. preparative silica gel chromatography.
• the second step may consist of reacting the alcohol toluene-4-sulfonate with the hydroxyl fatty acid ester in a suitable system of solvent, base and catalyst, e.g. in acetonitrile containing 1 equivalent potassium carbonate and 0.05 equivalents sodium iodide, in relation to the alcohol toluene-4-sulfonate.
• Purification of the produced alkyloxy acid ester can for example be done by extraction.
• the product is then washed with a weakly acidic solution, e.g. 1% sulphuric acid. If needed, farther purification may be done using a chromatographic method, e.g. preparative silica gel chromatography.
• One very advantageous succeeding step after the esterification or etherification of the HFA, yielding surprisingly pure products at high yield is when the obtained HFA derivatives are esterified with the polyoxyalkylene glycol, or monoalkylated polyoxyalkylene glycol using a hydrolytic enzyme, and this enzyme is having the capability of catalyzing ester formation between the carboxylic group of the HFA derivative and the ending hydroxyl group of POAG or POAG-derivative, without catalyzing any reaction with existing ester or ether bond on the O-acyl/allyl/alkenyl-HFA. This is in the following some times referred shortly to as “enzymatic POAGylation”.
• lipase B from Candida antarctica or an equivalent can be used.
• a preferred enzyme to be used in the inventive process is lipase B from Candida antarctica .
• the most preferred form of the enzyme to be used in the inventive process is the immobilized form of the lipase B enzyme from Candida antarctica.
• the enzymatic POAGylation step is advantageously performed in combination with the use of vacuum to remove water or any other volatile co-product formed during the esterification.
• This enzymatic POAGylation step can advantageously be performed without the presence of any organic solvents, i.e. a solvent-free reaction step.
• the reaction can be monitored by using HPLC.
• HPLC high-density polyethylene glycol
• a preferred option is to choose reversed phase chromatography, using an evaporative light scattering detector.
• Reaction temperatures when utilizing lipase B from Candida antarctica are typically between 50 and 90 degrees Celsius.
• the compounds of the invention may be incorporated for different purposes in formulations, thereby taking advantage of their benefits as described above.
• Such purposes include usages as; surface active agents, solubilizers, detergents, dispersants for liquid dispersions, solid dispersants, emulsifiers, carriers, freeze-drying additives, spray-drying additives and wetting agents.
• the compounds of the invention can be used in combination with any other compound not being negatively influenced by their presence. Especially it is foreseen to use them in combination with compounds in water being (according to definition given in US Pharmacopoeia 24, from 2000, page 10) sparingly soluble or less soluble. This includes sparingly soluble, slightly soluble, very slightly soluble, practically insoluble and insoluble, according to the same definition. Thus it includes compounds having a solubility of less than approx. 0.033 mg/mg in a solvent, corresponding to 33 mg/ml in water.
• the solvent in relation to this invention is water, at 25 degrees Celsius and normal atmospheric pressure.
• the compounds of the invention may be incorporated in pharmaceutical formulations for any purpose known according to the art, thereby taking advantage of their benefits as described above.
• Such purposes include, but are not limited to using them as; surface active agents, solubilizers, emulsifiers, carriers, solid dispersants, dispersants for liquid dispersions, wetting agents, lubricants, freeze-drying additives, spray-drying additives, etc.
• parenteral formulations e.g. subcutaneous, intravenous, intramuscular, intraperitoneal, intraarterial, intracerebrovascular
• oral formulations rectal formulations
• topical formulations e.g. subcutaneous, intravenous, intramuscular, intraperitoneal, intraarterial, intracerebrovascular
• buccal formulations e.g. sublingual formulations, this enumeration not intended to be limiting in any way.
• Preferred formulations are oral, topical, rectal or parenteral. More preferred formulations are oral or parenteral. Most preferred is parenteral formulations.
• Non-limiting examples of oral formulations suitable for use with compounds of the invention are tablets, effervescent tablets, capsules, granules, pellets, powders, sachets, dispersions, suspensions, emulsions, microemulsions, self-emulsifying systems and solutions.
• the formulator may need to include various excipients, such as cosolvents, buffers, polymers, disintegrants, fillers/diluents, stabilisers and preservatives.
• the compounds of the invention can be used in combination with any pharmaceutically active ingredient (drug) or vitamin not being negatively influenced by their presence. Especially is it foreseen to use them in combination with drugs or vitamins in water being (according to definition given in US Pharmacopoeia 24, from 2000, page 10) sparingly soluble or less soluble. This includes sparingly soluble, slightly soluble, very slightly soluble, practically insoluble and insoluble, according to the same definition. Thus it includes drugs or vitamins having a solubility of less than approx. 33 mg/mg in a solvent, corresponding to 33 mg/ml in water.
• the solvent in relation to this invention is water, at 25 degrees Celsius and normal atmospheric pressure.
• the pharmaceutical formulations may comprise one or more compound according to the invention, and may also contain more than one pharmaceutically active ingredient. It is further possible for the pharmaceutical formulations (utilizing the invention) to comprise one or more vitamin. Another aspect that is contemplated is that combinations of one or more vitamin with one or more pharmaceutically active ingredient may be used in the formulations of the invention.
• a preferred embodiment of pharmaceutical formulation according to the invention comprises one or more drug or pharmaceutically active ingredient selected among; Proton pump inhibitors, calcium channel blockers, adrenergic beta-blockers, anesthetics, steroids, antioxidants, renin inhibitors, alkaloids, cytostatics, anticoagulants, lipid regulating agents, anti-depressants, neuroleptics, immunosuppressants, immunomodulators, antibiotics and non-steroidal antiinflammatory agents.
• Proton pump inhibitors selected among; Proton pump inhibitors, calcium channel blockers, adrenergic beta-blockers, anesthetics, steroids, antioxidants, renin inhibitors, alkaloids, cytostatics, anticoagulants, lipid regulating agents, anti-depressants, neuroleptics, immunosuppressants, immunomodulators, antibiotics and non-steroidal antiinflammatory agents.
• 7.5 mmol (3.7 g) of the obtained ethyl 12-lauroyloxy-stearate and 75 mmol (45 g) PEG600 were mixed with 50 mg immobilized lipase B from C. antarctica (Novozym 435 from Novozymes A/S Denmark) in a 250 ml round flask with stirring under vacuum ( ⁇ 1 mm Hg) at 60° C. for 16 h.
• the reaction was monitored using reversed phase HPLC with a Supelco Discovery C18-column (4.6 mm i.d. ⁇ 150 mm), 1 ml/min of a 95:5 methanol:water mixture with addition of 0.5% acetic acid in the separation. Detection was done with a Sedex 45 evaporative light scattering detector (Sedere, Alfortville, France) at 30° C. and 2 bar air pressure.
• the 12-hydroxystearic acid was from the same origin and purified as in the preceding examples.
• the 12-hydroxystearic acid was from the same origin and purified as in the preceding examples.
• the general reaction route is: palmityl alcohol ⁇ palmityl toluene-4-sulfonate ⁇ ethyl 12-palmityloxy-stearate ⁇ PEG1500 mono-12-palmityloxy-stearate
• the general reaction route is: 12-hydroxystearic acid ⁇ ethyl 12-hydroxystearate ⁇ ethyl 12-stearoyloxy-stearate ⁇ BuPPG2500 12-stearoyloxy-stearate
• BuPPG2500 polypropylene glycol monobutyl ether of average molecular weight 2500 g/mol
• Isolated yield is calculated based on the fatty acid reactant.
• monoesters with short PEG or MePEG chains caused hemolysis at low concentrations.
• PEG600 mono-12-propionyloxystearate, PEG600 mono-12-hexanoyloxystearate and PEG600 mono-12-octanoyloxystearate caused total haemolysis at concentrations below 1 mM.
• MePEG550 mono-12-hydroxystearate (a compound representing the compounds disclosed in U.S. Pat. No. 6,365,637 B1, Zirnstein et al) caused profound hemolysis at 1 mM and total hemolysis at 5 mM.
• the commercial product Tween 80 caused haemolysis at concentrations around 5 mM and above.
• the monoesters with longer PEG and MePEG chains did not cause any haemolysis at all up to 10 mM, except for PEG1500 mono-12-lauroyloxy-stearate which caused total hemolysis already at 5 mM.
• TEER transepitheliar electrical resistance
• the solubilization capacity of the compounds of the invention and compounds of prior art for two poorly soluble (i.e. less than sparingly soluble) drug molecules, felodipine and griseofulvin were tested.
• the solubilization capacity for each surfactant was determined from the slope of the curve in a graph where the felodipine/griseofulvin concentration was plotted against the surfactant concentration at surfactant concentrations above CMC (critical micellar concentration).
• Solutol HS15 is a commercial product and is used as a reference.
• ⁇ G ⁇ F Compound M/M M/M Solutol HS 15 0.015 0.15 PEG1500 mono-12-lauroyloxy-stearate 0.034 0.13 PEG1500 mono-12-myristoyloxy-stearate 0.044 0.31 PEG1500 mono-12-palmitoyloxy-stearate 0.032 0.32 PEG1500 mono-12-stearoyloxy-stearate 0.058 0.29
• the tablet are constructed according to the hydrophilic gel matrix principle.
• solution I comprising felodipine (active ingredient), propyl gallate and the surfactant PEG 1500-mono-12-palmitoyloxy-stearate, was made.
• the powders (III) were mixed in a mixer and moistened with Solution I until homogeneity.
• the obtained granulate was dried in a drying oven.
• the granulate obtained was mixed with the powder IV, the lubricant, and mixing was continued for a total of 3 minutes.
• the mixture was compressed to tablets having an average weight of 227 mg, on a tabletting machine, using 9 mm circular concave punches.
• Tablets compressed at 17 kN having an average hardness of 71 N were tested for dissolution of felodipine, using a USP dissolution apparatus No. 2 (paddle), equipped with stationary baskets, operated at 100 rpm.
• the tablets are constructed according to the hydrophilic gel matrix principle.
• the tablets are prepared according to Example 14, except that the surfactant used in Example 14, PEG1500 mono-12-palmitoyloxy-stearate is exchanged to MePEG2000 12-stearoyloxy-stearate.
• the tablets are constructed according to the hydrophilic gel matrix principle.
• the tablets are prepared according to Example 14, except that the surfactant used in Example 14, PEG1500 mono-12-palmitoyloxy-stearate is exchanged to MePEG 1200 12-palmitoyloxy-stearate.
• the tablets are constructed according to the hydrophilic gel matrix principle.
• the tablets are prepared according to Example 14, except that the surfactant used in Example 14, PEG1500 mono-12-palmitoyloxy-stearate is exchanged to PEG1500 mono-12-oleoyloxy-stearate.
• the tablets are constructed according to the hydrophilic gel matrix principle.
• the tablets are prepared according to Example 14, except that the surfactant used in Example 14, PEG1500 mono-12-palmitoyloxy-stearate is exchanged to BuPPG2500 12-stearoyloxy-stearate.
• felodipine 5 g felodipine is dissolved in 150 g melted MePEG2000 12-stearoyloxy-stearate.
• the melt continuously stirred
• the capsules are cooled under controlled conditions.
• 0.5 g felodipine and 1.0 g soybean lecithin are dissolved in 98.5 g soybean oil.
• 5 g PEG1500 mono-12-palmitoyloxy-stearate is dissolved in 895 g of water for injection.
• a coarse emulsion is formed by mixing the oil phase with the aqueous phase using an ultraturrax mixer. The droplet size is further decreased by high-pressure homogenisation.
• SEDDS Self-emulsifying Drug Delivery Systems
• felodipine 5 g felodipine is dissolved in a molten mixture of 175 g PEG1500 mono-12-palmitoyloxy-stearate and 175 g PEG2000 and the mass is cast in appropriate moulds.

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• Oil, Petroleum & Natural Gas (AREA)
• Inorganic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Enzymes And Modification Thereof (AREA)
• Polyethers (AREA)
• Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)

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• 2003
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• 2004
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